Thyroid & Multiple Endocrine Neoplasia type 2 (MEN2)

The most common place that an endocrine cancer will occur is in the thyroid gland. Approximately 1.2% of Americans will be diagnosed with thyroid cancer in their lifetime. Thyroid cancer is three times more common in women than in men, and while it can be diagnosed at any age, most diagnoses will occur in the 40-50s (women) or 60-70s (men). Iodine deficiency and therapeutic radiation exposure in childhood are well established risk factors for thyroid cancer. However, as with most cancers, a specific cause for the great majority of thyroid cancers cannot be identified. Rather it is likely that there are multiple factors which play a part in the development of the cancer.

Most thyroid cancers are described by three major subtypes (SEER Cancer Statistics): papillary (90%), follicular (5%), and medullary (2%). Other rare types of thyroid cancer that make up the remaining 3% include Hurthle cell, anaplastic, and thyroid lymphomas/sarcomas.

A genetic predisposition to thyroid cancer is rare, and the chance for an underlying hereditary risk factor depends on the type of thyroid cancer someone has. Only about 5% of non-medullary thyroid cancers (follicular and papillary) are due to a single gene predisposition. Of those 5%, the genes that can contribute to thyroid cancer include: APC (familial adenomatous polyposis syndrome), PTEN (Cowden syndrome), DICER1, CHEK2, PRKAR1A, TP53, and WRN. An isolated case of non-medullary thyroid cancer is unlikely to be hereditary unless there are other cancers in the family.

Multiple Endocrine Neoplasia, type 2 (MEN2)

Unlike non-medullary thyroid cancers, as many as 30% of individuals with medullary thyroid cancer (MTC) have a hereditary cause due to multiple endocrine neoplasia, type 2 (MEN2). MEN2 is caused by changes (called mutations) in the RET gene. Individuals with MEN2 are at an increased risk to develop MTC, pheochromocytomas of the adrenal glands (rare tumor that can make your adrenal glands produce more hormone than they’re supposed to), and parathyroid gland adenomas (benign tumors). MEN2 can be broken down into three subtypes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). All three subtypes have a 95-100% chance to develop MTC. Individuals with MEN2A and MEN2B also have a 50% chance to develop pheochromocytoma, while people with MEN2A also have a 20-30% chance to develop parathyroid disease.

RET gene mutations are inherited in an autosomal dominant pattern, meaning that children of a mutation carrier each have a 50% risk to inherit the mutation and associated cancer risks. Notably, women and men both have the RET gene and have the same chances to inherit and pass down mutations in these genes. Therefore, both sides of the family are important when assessing inherited risk. Some individuals do not have any affected family members, and may be the first person in their family to have MEN2. In MEN2A, about 95% of people also have an affected parent, so 5% are the first people in their family to have it. For MEN2B, about 50% of people also have an affected parent, so 50% are the first people in their family to have it. People who have FMTC have other affected family members by definition.

Diagnosis and genetic testing

MEN2 can be diagnosed by a doctor doing a clinical exam to look at someone’s medical and family history for certain patterns:

  • A clinical diagnosis of MEN2A is made when there two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma) in a single person, or in close relatives.
  • A clinical diagnosis of MEN2B is made when there is an early-onset MTC, mucosal neuromas (yellow-white painless bump) on the lips and tongue, and some distinctive physical features (larger lips, ‘marfanoid’ body habitus).
  • A clinical diagnosis of FMTC is made when there are four or more cases of MTC in the family, but there is no history of pheochromocytomas or parathyroid adenomas.

If clinical testing is not performed, or is not conclusive, then genetic testing for the RET gene can be helpful. There are a few different ways to approach testing:

  • Single site analysis: Testing specific to a known mutation in the family
  • Full gene sequencing and rearrangement analysis: Comprehensive testing to search for all currently detectable mutations in the RET gene
  • Gene panels: Newer, more broadly based gene tests that would include not only the RET gene, but other genes known or suspected to be associated with the patient’s underlying health concerns.

Determining whether an individual meets criteria for genetic testing for MEN2 is very complex, and would likely be best left to a genetic counselor or other healthcare provider.

Screening and Management Guidelines

Management for individuals with MEN2 is complex and largely individualized depending on the person’s medical and family history, as well as the specific gene change that they carry. Sometimes the specific change (or mutation) can tell us whether someone has MEN2A, MEN2B, or FMTC. The specific mutation can also tell us how high someone’s risk may be to develop related health concerns, and what age to begin certain types of screening. There may also be specific medications that your doctor may have you avoid if you have a diagnosis of MEN2. It is important to work with your doctor to develop the screening plan that will work best for you.

Additional Resources

American Multiple Endocrine Neoplasia Support (AMENSupport):

Last updated on Jan 22nd, 2019